tbuckley/cabot-search huggingface dataset:
Phase Ia dose-escalation study of the anti-BTLA antibody icatolimab as a monotherapy in patients with advanced solid tumor.
Authors: Russell J. Schilder, John D. Powderly, Haeseong Park, Mehmet Asim Bilen, Meredith McKean, Rena May, Hui Feng, Sheng Yao, Patricia Keegan, Aung Naing
Journal: Journal of Clinical Oncology (2022)

2643 Background: The B- and T-lymphocyte attenuator (BTLA) is an inhibitory receptor expressed on B, T and NK cells. Icatolimab (TAB004 or JS004) is a humanized IgG4 monoclonal antibody (mAb) with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand HVEM. In preclinical studies, icatolimab monotherapy suppressed tumor growth in murine tumor models using human BTLA knock-in mice. In this first-in-human dose-escalation study, we report the preliminary safety and efficacy of icatolimab as a single agent in patients with advanced solid tumors. Methods: Eligible patients with advance solid tumors refractory to standard therapies were enrolled in this study. Icatolimab was administered at escalating doses of 0.3, 1, 3 and 10 mg/kg intravenously Q3W and followed by dose expansion in 3 and 10 mg/kg cohorts until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated by a safety monitoring committee. Study objectives included safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Results: A total of 25 patients with solid tumor were enrolled in the Part A of this phase I study (NCT04137900). The median age was 62 (range 32-85) years with 16 (64%) male patients. Patients were heavily pretreated with a median of 4 prior lines of therapy. Fifteen (60%) patients received and progressed upon prior anti-PD-1/L1 therapy. By the data cutoff date of December 31, 2021, the median follow-up was 32 weeks. No DLT was observed. 24 (96%) patients experienced treatment emergent adverse event (TEAEs), with 7 (28%) experienced grade 3 TEAEs. No grade 4 or 5 TEAE occurred. The incidence or severity of AE was not associated with the dose. The most common TEAEs were fatigue (32%), abdominal pain (20%), diarrhea (16%), arthralgia (16%), aspartate aminotransferase increased (16%), constipation (16%), and contusion (16%). One (4%) TEAE led to discontinuation of study drug. Four (16%) patients experienced immune related AE. Among 19 evaluable patients by the cutoff date, 1 confirmed PR (melanoma) and 6 SD were observed as assessed by the investigator per RECIST v1.1. The response was still ongoing over 12 months in the melanoma patient who had progressed upon prior nivolumab and BRAF/MEK inhibitors treatments. BTLA receptor was fully occupied in the 3 and 10 mg/kg cohorts. The mean elimination half-life of icatolimab was 7.5 to 19.2 days in four dose cohorts. Biomarker analysis indicated co-expression of HVEM and CD8 was associated with favorable response. Conclusions: Icatolimab monotherapy were well tolerated in all doses evaluated and showed preliminary clinical efficacy as a monotherapy. Icatolimab in combination with toripalimab (anti-PD-1) for the treatment of patients with advanced solid tumors is currently ongoing. Clinical trial information: NCT04137900.
Outcomes of neoadjuvant (NA) and adjuvant (A) chemotherapy in geriatric patients with stage I-III triple-negative breast cancer (TNBC): A single institution experience.
Authors: Christine Sam, Marina Sehovic, Martine Extermann
Journal: Journal of Clinical Oncology (2022)

e12522 Background: Older breast cancer patients have greater risk for toxicity with perioperative chemotherapy and poorer outcomes for stage I-III TNBC due to medical comorbidities and declining organ function. It is not clear whether use of anthracycline based chemotherapy regimens (ABC) delivers better outcomes than non-anthracycline taxane-based chemotherapy regimens (TBC) in this population. Methods: A single institution retrospective review of TNBC patients ≥65 treated with adjuvant and neoadjuvant chemotherapy at Moffitt Cancer Center from 2009 to December 2018 was conducted. Demographic, comorbidity, treatment, and toxicity variables were collected. Treatment toxicity was defined as dose reductions, dose delays, early discontinuations, unplanned hospitalizations, and grade 3-4 heme and non-heme toxicities. Eligible patients had stage I-IIII TNBC, were ≥65, and received NA or A chemotherapy at MCC. A validated frailty index (FI) was used to calculate comorbidity score. Kaplan Meier was used to estimate overall survival by regimen received, with log rank test to compare ABC and TBC groups. Results: A total of 79 patients met criteria for analysis, with mean age of patients receiving treatment was 71 (range 65-88). 41.8% of patients had stage I disease, 36.7% with stage II, and 21.5% with Stage III. 76% of patients with Stage III, 51.7% of Stage II, and 18% of stage I disease received ABC. There was a trend toward higher toxicity events in patients receiving ABC compared to TBC regimens, although not statistically significant (see Table). The mOS for patients receiving ABC was 43.5mo and 63.0 mo for patients receiving TBC, although not statistically significant (p=0.212). Conclusions: Geriatric patients with stage I-III TNBC were mostly able to successfully receive NA or A chemotherapy, although TBC may have better tolerability. Patients receiving TBC also had better survival, although not statistically significant and potentially confounded by patients with earlier stage or less aggressive tumors receiving TBC.[Table: see text]
Efficacy and safety of capmatinib plus pembrolizumab in treatment (tx)-naïve patients with advanced non–small cell lung cancer (NSCLC) with high tumor PD-L1 expression: Results of a randomized, open-label, multicenter, phase 2 study.
Authors: Tony S. K. Mok, Diego Luigi Cortinovis, Margarita Majem, Melissa Lynne Johnson, Feby Ingriani Mardjuadi, Xuan Zhao, Sagar Vidya Siripurapu, Zhiqiang Jiang, Juergen Wolf
Journal: Journal of Clinical Oncology (2022)

9118 Background: Capmatinib is a selective MET inhibitor approved for patients (pts) with metastatic NSCLC harboring MET exon 14 skipping mutation. Pembrolizumab (pembro) is a programmed death protein-1 (PD-1) inhibitor approved as monotherapy for pts with advanced NSCLC expressing PD-ligand 1 (PD-L1). Preclinical studies have shown that capmatinib enhances T cell mediated antitumor response in mice treated with PD-1 inhibitors. Combining capmatinib with pembro may be beneficial in pts with advanced NSCLC expressing high tumor PD-L1. Methods: Herein we evaluated the efficacy and safety of capmatinib plus pembro (combo) versus pembro alone in tx-naïve pts with advanced MET-unselected NSCLC expressing PD-L1 with tumor proportion score (TPS) ≥50%, and no ALK or EGFR tumor aberrations. Pts received pembro 200 mg IV q3w in the pembro alone arm or with capmatinib 400 mg orally BID in the combo arm. The primary endpoint was investigator-assessed progression-free survival (PFS) using RECIST v1.1. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), pharmacokinetics and safety. Results: As of the data cut off (DCO) of 28 Feb 2021, 76 pts were randomized 2:1 to the combo arm (n = 51) or pembro alone arm (n = 25). Baseline demographics and disease status were mostly comparable across study arms. At this interim analysis, PFS data were not mature. Median PFS (95% CI) was 6.3 (3.2, not evaluable [NE]) months in the combo arm and 4.3 (2.3, NE) months in the pembro alone arm. The ORR (95% CI) was 15.7% (7.0%, 28.6%) and 28.0% (12.1%, 49.4%) in the combo and pembro alone arms, respectively. The DCR (95% CI) was comparable across study arms; combo: 56.9% (42.2%, 70.7%) and pembro alone: 56.0% (34.9%, 75.6%). In the combo arm, capmatinib exposure (C max : 3580 ng/mL [n = 7] and AUC tau : 19700 hr*ng/mL [n = 2]) was consistent with data from previous studies. Tx-related grade (GR) ≥3 adverse events (AEs) were more common in the combo (37.3%) vs pembro alone arm (16%). Tx-related AEs occurring in ≥10% of pts are shown in the Table. Tx discontinuation and dose adjustment/interruptions were more common in the combo (27.5% and 52.9%) vs pembro alone arm (16% and 16%). Capmatinib was stopped prematurely in the combo arm, and at DCO, 32 (62.7%) pts in the combo arm and 18 (72%) pts in the pembro alone arm were receiving pembro monotherapy. Conclusions: Combination tx with capmatinib and pembro was not well tolerated and did not improve antitumor activity in tx-naïve pts with advanced NSCLC with PD-L1 TPS ≥50%. Clinical trial information: NCT04139317. [Table: see text]
Different gene mutations among gastric cancer patients with MSS and MSI-H types in China.
Authors: Jianyong Zheng, Kunli Du, Guangming Ren, Zhenyu Xie, Ruikai Li, Gaozan Zheng, Fan Feng, Weiming Duan, Depei Huang, Hushan Zhang
Journal: Journal of Clinical Oncology (2022)

e16018 Background: Gastric cancer is one of the leading causes of cancer-related deaths worldwide, although the incidence has gradually decreased in many Western countries. The status of microsatellites is an important biomarker of gastric cancer immunotherapy, but not all patients with MSI-H have excellent curative effect. Therefore, this study of the molecular background of MSS and MSI-H, which is helpful for the development of gastric cancer immunotherapy in Chinese patients. Methods: The formalin-fixed paraffin-embedded (FFPE) tissues of 6603 patients with CRC who have underwent next-generation sequencing (NGS) from Jan, 2019 to Apr, 2021 in 3DMed Clinical Laboratory Inc. were investigated in this study. These patients are still being followed up. Statistical analysis was performed using Microsoft Office Excel (2013). Results: 7.0% (139/1997) patients with MSI-H status, MSI-H and MSS tumors showed striking gene mutation differences. Among the 10 genes with the highest mutation rate, TP53 ERBB2 CDH1 PIK3CA mutations appear in both MSI-H and MSS patients. But the mutation rates of these genes vary greatly (32.3% VS 53.7%, 19.4% VS 13.0%,12.2% VS 8.2%, 34.5% VS 8.2%, respectively). Among the top 10 mutated genes, ARID1 (70.5%), mutation with the highest rate is only mutated in MSI-H patients. There are other gene mutations, including KMT2C (68.3%), RNF43 (59.7%), TGFBR2 (58.3%), RNF43 (34.5%), MSH3 (46.8%), RAD50(41.0%), MSH6(31.7%), ATR (30.2％), which have hugely higher mutation rates than MSS patients. It is worth noting that the mutation rate of TP53, BCL2L11, CYP2C19, MYC, CCNE1 and UGT1A1 in MSS patients is absolutely higher than that in MSI-H. Conclusions: There are completely differences in gene mutations between MSI-H and MSS gastric cancer patients in the Chinese population, especially TP53, ERBB2, CDH1, PIK3CA KMT2C, RNF43, TGFBR2, RNF43, MSH3, RAD50, MSH6 and ATR, which are of great significance for accurate patient stratification and treatment.
Bringing experimental therapeutics clinical trials network (ETCTN) to underrepresented population.
Authors: Joaquina Celebre Baranda, Gary C. Doolittle, Rahul Atul Parikh, Anup Kasi, Elizabeth Marie Wulff-Burchfield, Benjamin Powers, Robert E. Pluenneke, Marc Steven Hoffmann, Abdulraheem Yacoub, Anwaar Saeed, Larry R. Corum, Tara L. Lin, Weijing Sun, Margaret M. Mooney, Jeffrey Moscow, James H. Doroshow, Brittany Waters, S. Percy Ivy, Steven Gore, Roy A. Jensen
Journal: Journal of Clinical Oncology (2022)

6542 Background: Access to health care including clinical trials (CT) leading to paradigm-changing cancer treatments are critical for high quality cancer care and equity in society. In this report, we highlight methods in accruing to ETCTN wherein underrepresented rural, low-income, and racial minorities comprise &gt;50% of enrollment. Methods: University of Kansas Cancer Center (KUCC) is one of eight National Cancer Institute (NCI) designated cancer centers awarded CATCH-UP.2020 (CATCH-UP), a congressionally mandated P30 supplement to enhance access for minority/underserved populations to ETCTN precision medicine CT. KUCC catchment area is 23% rural by Rural Urban Continuum Codes (RUCC); almost 90 % of counties are designated primary care HPSA’s (Health Professional Shortage Areas). KUCC Early Phase and Masonic Cancer Alliance (rural outreach network) partnered to operationalize CATCH-UP. We engaged disease-focused champion investigators in disease working groups and MCA physicians who selected scientifically sound CT that fit catchment area needs. Patient and Investigator Voices Organizing Together, a patient research advocacy group provided practical feedback. MCA navigator coordinated recruitment. Telehealth was used for rural patients that would have a significant distance to travel just to be screened. Results: CATCH-UP was initiated in September 2020. Twenty-eight CT were activated, many in community sites. Average activation time was 81 days. Delays were mainly from CT amendments. KUCC enrolled the first patient in the CATCH-UP program. In 6 months, we met accrual requirements (24/year, 50% minorities). During first year, we enrolled 47 (&gt;50% minorities), an increase of 680% from our average accrual of 6/year (&gt;50% minorities) in ETCTN through Early Drug Development Opportunity Program (2016-2020). To date, we have enrolled 61, 54% from rural, HPSA, race and other minorities. Although the proportion of minorities did not change but remained high, this funding allowed us to substantially increase the number of patients from a catchment area with high proportion of geographically and socioeconomically underserved minorities given access to early phase CT through ETCTN. Conclusions: Amid COVID-19 pandemic, the NCI CATCH-UP program and methods we used allowed access to novel therapies for rural, medically underserved, and other minority groups. Funded by NIH: 3P30CA168524-09S2.
Effect of traditional Chinese medicine on pyrotinib-associated diarrhea in patients with HER2-positive breast cancer.
Authors: Zhansheng Jiang, Yanfang Yang, Hao Wang, Zhongsheng Tong, Zhanyu Pan
Journal: Journal of Clinical Oncology (2022)

e24096 Background: Pyrotinib, an irreversible pan-HER tyrosine kinase inhibitor, has been a salvage regimen for metastatic HER2+ breast cancer failed to trastuzumab in Chinese guidelines. However, the incidence of pyrotinib induced diarrhea is more than 80% as neratinib. TCM-padia001 (clinicaltrials.gov: NCT04988165) is an open-label, phase II study investigating the effectiveness of Traditional Chinese Medicine (TCM) in treating diarrhea and improving tolerability of pyrotinib. Methods: All patients in the group had diarrhea after taking pyrotinib, and they could not be controlled after previous use of other antidiarrheal drugs (loperamide, Bifidobacterium, montmorillonite powder). All patients were treated with oral TCM (a Chinese herbal formula, one dose per day divided in two times) for 3 weeks. Diarrhea assessment was graded according to NCI-CTCAE v5.0 and quality of life was graded according to EORTC QLQ-C30. The primary endpoint was incidence of grade ≥3 diarrhea. Results: A total of 28 patients were enrolled, and 23 patients completed 3 weeks of TCM treatment and were followed up. The median number of diarrheas was 7 times (4-13), and 15 cases in these 23 patients were ≥grade 3 before treatment with TCM. After treatment with TCM, none of patients had grade 3 diarrhea, and the rate of grade 2 diarrhea was 17.4% (4/23). The scores of global health status/quality-of-life assed with EORTC QLQ-C30 in patients were dramatically improved (40.90+7.68 vs. 62.88+7.15) after treatment with TCM. Most importantly, in the symptom domains scores, we found that TCM treatment did not increase the incidence of constipation, but also significantly improved the fatigue, pain, nausea, vomiting and anorexia of patients. Conclusions: TCM is very effective in the treatment of Pyrotinib related diarrhea, and compared with Western antidiarrheal drugs, it will not produce secondary painful symptoms such as constipation. Clinical trial information: NCT04988165.
Assessing homologous recombination deficiency (HRD) in ovarian cancer: Optimizing concordance of the regulatory-approved companion diagnostic and a next-generation sequencing (NGS) assay kit.
Authors: Wilko Weichert, Ping Qiu, Jared Lunceford, Amy Wehn, Alexander Yarunin, Razvan Cristescu, Li Liu, Kyria Roessler, Kirsten Timms, Matthew John Marton
Journal: Journal of Clinical Oncology (2022)

e17571 Background: Olaparib + bevacizumab is approved as first-line maintenance treatment of ovarian cancer that is HRD positive, defined as the presence of a deleterious/suspected deleterious BRCA mutation (BRCAm) and/or genomic instability. HRD genomic instability score (GIS) has been assessed in clinical trials using a regulatory-approved companion diagnostic, Myriad myChoice ® CDx. We evaluated the performance of an in-development NGS assay kit that identifies BRCA variants based on genomic content from Illumina’s TruSight™ Oncology 500 research assay, and, with additional genomic content, measures HRD GIS in tumor tissue (Illumina test) in parallel. Analytic concordance of the Illumina test versus the Myriad myChoice ® PLUS assay (Myriad test) under improved algorithms for calculating GIS scores is reported. Methods: Ovarian cancer tissue samples were analyzed with the Illumina (40 ng DNA; N = 227) and Myriad (200 ng DNA; N = 254) tests. Agreement rates for BRCA analysis, HRD GIS, and overall HRD status (includes BRCAm and HRD GIS [cutoff, 42]) were analyzed. For the overall and the non-BRCAm analysis cohorts, Pearson correlation between the continuous HRD GIS of the Illumina and Myriad tests was determined. Analytic sensitivity and specificity of the Illumina-derived HRD GIS to classify HRD GIS (cutoff, 42) were evaluated using AUROC. After initial concordance calculations, modifications were made to increase the quality of the Illumina preprocessing data (ie, reducing allele dosage noise and allele bias) upstream of the GIS calling algorithm. Reprocessing of the existing raw data led to further improvement in the point estimates of positive and negative percent agreement. Results: Prevalence using the Illumina and Myriad tests was 51.2% and 49.2% (overall HRD positive) and 27.6% and 25.5% (BRCAm), respectively. Agreement rates are reported in the Table. Correlation of the Illumina HRD GIS with Myriad HRD GIS was 0.980 (all samples) and 0.976 (non-BRCAm cohort); AUROCs were 0.995 and 0.992, respectively. Conclusions: Comparison between the Illumina and Myriad tests showed that overall HRD status, BRCA analysis, and HRD GIS detection results were &gt; 90% concordant; HRD GIS was highly correlated (r &gt; 0.98); and prevalence estimates were similar. These data suggest that a distributable kit solution, such as the Illumina test under development, will approach the performance of the Myriad myChoice HRD assay.[Table: see text]
A phase III randomized trial of eribulin (E) with or without gemcitabine versus standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937.
Authors: Sarmad Sadeghi, Melissa Plets, Primo "Lucky" N. Lara, Catherine Tangen, Rick Bangs, Seth P. Lerner, Thomas W. Flaig, Daniel P. Petrylak, Ian Thompson
Journal: Journal of Clinical Oncology (2022)

TPS4608 Background: UC is 2nd most common genitourinary cancer. Current SOC offers platinum-based (PB) first line chemotherapy (chemo) with ddMVAC or gemcitabine-cisplatin (GC) regimens. For cisplatin ineligible patients (pts), SOC includes gemcitabine-carboplatin (GCa), and in select pts pembrolizumab. Erdafitinib is approved for pts with FGFR alterations and Enfortumab vedotin (EV) is approved for previously treated pts. A phase I/II CTEP study of eribulin (E) for metastatic UC (mUC) established the activity of E in UC with objective response rate (ORR) of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N = 150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N = 24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 5 responders in 7 pts for GE vs 12 out 49 E. Methods: This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. In the GE arm, gemcitabine is added to E at 1000 mg/m2 dose to D1 and D8. SOC follows standard dosing of the agents. There is no limit to the number/sequence of prior regimens. A simplified summary of eligibility criteria is presented here. All pts must have: received frontline systemic treatment such as PB chemo or a non-platinum regimen. received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab. received EV. Assuming a median OS for the SOC arm of 7 mo the study seeks to find at least a 50% increase in median OS to 10.5 mo (Hazard Ratio (HR) = 0.667). One-sided 0.0125 type I error to account for testing of two primary hypotheses (Each arm vs. SOC). 87% power to detect a 3.5 mo improvement in OS. We require 140 eligible (155 total) pts in each arm for a total of 465. The study was activated in Feb 2021 and accrual is ongoing. Clinical trial information: NCT04579224.
Overall survival of children with brain tumors after radiation therapy in Kazakhstan.
Authors: Zaure Dushimova, Alyona Goncharova, Dilyara Kaidarova, Sabina Kopochkina
Journal: Journal of Clinical Oncology (2022)

e22011 Background: Tumors of the central nervous system in children occupy the 2nd place in frequency in the structure of malignant neoplasms of childhood and the 1st place among solid tumors. They make up about 20% of all malignant neoplasms of childhood and are mainly represented by brain tumors. The purpose of the study was to analyze the survival rate depending on various factors during radiation therapy (RT) of brain tumors in children. Methods: Retrospective study included 277 patients who received RT from 2016 to 2020 at the Pediatric Oncology Center of the Kazakh Research Institute of Oncology and Radiology. The average follow-up time was 34.3 months. The median age was 9.5 years. RT was performed on a linear accelerator “TrueBeam”, in a single dose of 1.8 Gy, total 50.4-54.0 Gy, 5 fractions per week. Survival distributions was estimated by Kaplan and Meier curves and survival differences were evaluated using the log-rank test. IBM SPSS Statistics V23 was used for statistical analyses. Results: The overall survival (OS) rate of 277 patients was 70.8%, with an average life time of 55.6 months, 95% confidence interval (CI) (51.9 - 59.2). Children under 10 years of age showed a 12.5 % worse OS compare to children after 10 years of age. In patients with unconfirmed morphological verification, OS is 31.5% worse than in children with confirmed morphological verification. In children with grade I-II tumor differentiation, OS was 30.6% higher than in children with grade III-IV tumors. The method of RT (conformal RT, IMLT), gender of patients did not have a statistically significant effect on OS. Conclusions: Our study showed that OS rate depends on various factors, such as age, presence of morphology verification, and the degree of tumor differentiation. RT allows to achieve better survival in patients older than 10 years who received RT with a morphologically confirmed diagnosis of GI-II. RT is one of the main treatments for brain tumors in children.[Table: see text]